This invention relates to organoplatinum complexes and, more particularly, to 1,2-diaminocyclohexane platinum (II) complexes having antineoplastic activity against the L1210 mouse leukemia test system.
In the last several years, a number of organoplatinum complexes have been synthesized and reported as potentially active antitumor agents. One of these compounds, cis-dichlorodiammineplatinum (II), has been utilized with limited success in cancer chemotherapy of man, but due to its toxic side effects, has a rather low therapeutic index.
Subsequent efforts to find other organoplatinum complexes having higher therapeutic index values led to the synthesis and testing of dichloro (1,2-diaminocyclohexane) platinum (II) and also malonato (1,2-diaminocyclohexane) platinum (II). Connors et al (Chem.-Biol. Interactions, Volume 5, pages 415-424, 1972) assessed antitumor activity of dichloro (1,2-diaminocyclohexane) platinum (II) against the ADJ/PC6A plasma cell tumor in mice, and reported LD.sub.50, ID.sub.50, and therapeutic index values quite similar to those of cis-dichlorodiammineplatinum (II). Cleare et al (Bioinorganic Chemistry, Volume 2, pages 187-210, 1973) investigated the antitumor activity against the Sarcoma 180 in Swiss mice, of both dichloro (1,2-diaminocyclohexane) platinum (II) and malonato (1,2-diaminocyclohexane) platinum (II), and found both of these complexes to have only marginal antitumor activity and to be much less active than cis-dichlorodiammineplatinum (II). Neither Connors et al nor Cleare et al presented any data on the effects of these complexes on the more highly predictive L1210 leukemia in mice, nor did they use these complexes in combination chemotherapy with other antineoplastic agents.
In an extension of the work reported by Connors et al and Cleare et al, the present inventors and co-workers (Gale et al, Research Communications in Chemical Pathology and Pharmacology, Volume 7, No. 3, pages 529-538, March 1974) demonstrated that dichloro (1,2-diaminocyclohexane) platinum (II) was highly effective against L1210 leukemia in mice, providing an increase of up to 54 percent in mean survival time in comparison with cis-dichlorodiammineplatinum (II), and furthermore that it could be combined synergistically with the known antineoplastic agent cyclophosphamide. These results were very encouraging since effectiveness against the L1210 leukemia in mice is generally considered as being a highly predictive indication of a potentially clinically useful antineoplastic agent. However, one serious drawback to the potential clinical utility of dichloro (1,2-diaminocyclohexane) platinum (II) is the fact that this complex is very insoluble in aqueous i.v. fluids, necessitating its administration intraperitoneally as a slurry in water. Since intravenous, rather than intraperitoneal, administration is generally required for clinical effectiveness, a clinically useful antineoplastic agent should have sufficient water-solubility for use in aqueous i.v. fluids.